The G2-to-M transition from a phosphatase perspective: a new vision of the meiotic division

Abstract

Cell division is orchestrated by the phosphorylation and dephosphorylation of thousands of proteins. These posttranslational modifications underlie the molecular cascades converging to the activation of the universal mitotic kinase, Cdk1, and entry into cell division. They also govern the structural events that sustain the mechanics of cell division. While the role of protein kinases in mitosis has been well documented by decades of investigations, little was known regarding the control of protein phosphatases until the recent years. However, the regulation of phosphatase activities is as essential as kinases in controlling the activation of Cdk1 to enter M-phase. The regulation and the function of phosphatases result from post-translational modifications but also from the combinatorial association between conserved catalytic subunits and regulatory subunits that drive their substrate specificity, their cellular localization and their activity. It now appears that sequential dephosphorylations orchestrated by a network of phosphatase activities trigger Cdk1 activation and then order the structural events necessary for the timely execution of cell division. This review discusses a series of recent works describing the important roles played by protein phosphatases for the proper regulation of meiotic division. Many breakthroughs in the field of cell cycle research came from studies on oocyte meiotic divisions. Indeed, the meiotic division shares most of the molecular regulators with mitosis. The natural arrests of oocytes in G2 and in M-phase, the giant size of these cells, the variety of model species allowing either biochemical or imaging as well as genetics approaches explain why the process of meiosis has served as an historical model to decipher signalling pathways involved in the G2-to-M transition. The review especially highlights how the phosphatase PP2A-B55δ critically orchestrates the timing of meiosis resumption in amphibian oocytes. By opposing the kinase PKA, PP2A-B55δ controls the release of the G2 arrest through the dephosphorylation of their substrate, Arpp19. Few hours later, the inhibition of PP2A-B55δ by Arpp19 releases its opposing kinase, Cdk1, and triggers M-phase. In coordination with a variety of phosphatases and kinases, the PP2A-B55δ/Arpp19 duo therefore emerges as the key effector of the G2-to-M transition.

Translational Control of Xenopus Oocyte Meiosis: Toward the Genomic Era

“…In prophase-arrested fully-grown oocytes, the action of PP2A-B55δ on Arpp19 is overwhelmed by PKA activity, resulting in Arpp19 phosphorylation at S109. In response to progesterone or PKI injection, PKA activity decreases, allowing PP2A-B55δ to efficiently dephosphorylate Arpp19 [49][50][51]. This event is critical for meiosis resumption as the overexpression of a phosphomimic mutant form of Arpp19 (S109D) impairs Cdk1 activation induced by either progesterone or PKI [49].…”

HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression

“…To investigate the underlying mechanisms, we tested multiple cell cycle‐related proteins in SHMT1‐overexpression RCC cells. The G2/M check points‐related proteins such as p‐CDC25, p‐CDK1, and cyclin B/D/E were decreased, 27 suggesting SHMT1‐induced cell cycle arrest was due to the conventional signaling pathway. Interestingly, cell division cycle protein 20 (CDC20) was also decreased, which suggested a defect of chromosome segregation during mitotic exit (Figure S1C ).…”

Regulation of Oocyte Meiotic Maturation: Unraveling the Interplay between PKA Inhibition and Cdk1 Activation

“…This second step relies on a complex network of feedback loops involving many well-characterized kinases and phosphatases. The core of this so-called MPF autoamplification loop is the activation of Cdc25 phosphatase that dephosphorylates and activates the stockpiled pre-MPF, as well as the inactivation of Myt1, preventing the inhibitory phosphorylation of Cdk1 [12]. Once Cdk1 is fully activated, the oocyte undergoes NEBD, then enters in metaphase I (MI), achieves an asymmetric division by extruding the first polar body, enters in metaphase II (MII) and arrests again with a stable MII spindle, waiting for fertilization.…”